Throughout the world, gastrointestinal (GI) infections are a major cause of morbidity and mortality in humans. Etiologic agents include a range of aerobic and anaerobic bacterial and parasitic species. A leading treatment for these infections is the nitroimidazole drug metronidazole that is marketed as Flagyl® and is either used alone or in combination with other therapeutic drugs. Metronidazole has been in clinical use for more than 50 years.
One of the principal infections treated by metronidazole is mild-to-moderate Clostridium difficile infection (CDI). CDI is the leading cause of antibiotic-associated diarrhea in hospitals and is now a major public health problem in developed countries such as the United States and Europe.
Metronidazole benefits from being potent against C. difficile, demonstrating bactericidal properties, but is primarily for mild to moderate cases of CDI. The key issue with the use of metronidazole in more severe cases of CDI is that it is highly absorbed from the gastrointestinal tract. Metronidazole is so highly absorbed (>80% in 1-2 h) from the gastrointestinal tract that only low concentrations of the drug occur at the site of infection in the gastrointestinal tract. In cases of severe CDI more than 25% of patients typically relapse following metronidazole therapy.
Other gastrointestinal diseases that are treated with metronidazole may also experience sub-optimal treatment due to the low gastrointestinal concentration of the drug. These diseases include but are not limited to anaerobic bacterial and parasitic infections such as Amebiasis, Giardiasis, infections from Helicobacter pylori and Gardnerella, and Crohn's and other inflammatory bowel diseases.
It would be advantageous for the treatment of gastrointestinal infections and conditions to be able to administer a drug that has excellent effectiveness that also remains in the GI tract for a long time period. In particular, it would be beneficial for the treatment of CDI and other gastrointestinal infections and conditions to have a drug that has excellent anti-bacterial effectiveness that also remains in the GI tract for a long time period. For example, it would be advantageous to provide a drug having the anti-bacterial activity of metronidazole, but which is not readily absorbed from the GI tract.
Low or non-absorbed compounds bearing a nitroimidazole group, such as metronidazole, could represent a more efficacious treatment approach for CDI and other gastrointestinal conditions. The ability to achieve high local concentrations could also lower the prospects for resistance to emerge and, by lowering systemic exposure, prevent or reduce common known side effects associated with metronidazole and other nitroimidazoles.